Steroid-sensitive Nephrotic Syndrome Research Articles

The value of urinary soluble urokinase plasminogen activator receptor (suPAR) in children with nephrotic syndrome

<abstract><sec> <title>Objectives</title> To investigate the value of urinary suPAR with steroid responsiveness in childhood nephrotic syndrome (NS). </sec><sec> <title>Methods</title> A longitudinal follow-up study was carried out in 92 children diagnosed with nephrotic syndrome (49 initial NS and 43 relapsed NS). </sec><sec> <title>Results</title> The urinary suPAR/creatinine ratio was significantly high in the relapsed NS group (with a mean = 628 (386–1015) pg/µmol) compared with the initial NS group (mean = 509 (237–840) pg/µmol) and the control group (mean = 248 (88–609) pg/µmol) (p = 0.001). In the initial group, the concentration of urinary suPAR/creatinine ratio was higher in steroid-resistant NS (SRNS) than in steroid-sensitive NS (SSNS) after 6 weeks and 6 months of treatment, but the difference was not significant (p &gt; 0.05). In the relapsed NS group, the concentration of urinary suPAR/creatinine ratio was higher in SRNS than that in SSNS (p = 0.02). The urinary suPAR/creatinine ratio had sensitivity (73.9%) and specificity (89.5%) at the cut-off point of 950 pg/µmol to predict SRNS (p &lt; 0.001). </sec><sec> <title>Conclusions</title> Urinary suPAR could help distinguish the steroid responsiveness between SRNS and SSNS in children. </sec></abstract>

Steroid sensitive nephrotic syndrome: Revised guidelines

Justification: Steroid-sensitive nephrotic syndrome (SSNS) is one of the most common chronic kidney diseases in children. These guidelines update the existing Indian Society of Pediatric Nephrology recommendations on its management. Objective: To frame revised guidelines on diagnosis, evaluation, management, and supportive care of patients with the illness. Process: The guidelines combine evidence-based recommendations and expert opinion. Formulation of key questions was followed by review of literature and evaluation of evidence by experts in two face-to-face meetings. Recommendations: The initial statements provide advice for evaluation at onset and follow-up and indications for kidney biopsy. Subsequent statements provide recommendations for the management of the first episode of illness and of disease relapses. Recommendations on the use of immunosuppressive strategies in patients with frequent relapses and steroid dependence are accompanied by suggestions for step-wise approach and plan of monitoring. Guidance is also provided regarding the management of common complications including edema, hypovolemia, and serious infections. Advice on immunization and transition of care is given. The revised guideline is intended to improve the management and outcomes of patients with SSNS and provide directions for future research.

Clinical Pattern and Course of Nephrotic Syndrome in Children: An Observational Study

Introduction: Chronic renal diseases not only affects the personal life of an individual but also results in social and financial burden on their families too. Nephrotic syndrome is most common in the paediatric age group contributing to significant illness related morbidity and even mortality if not identified early and treated promptly. This common disease has shown varying clinical trends with studies attempting to document them. Aim: To study the clinical pattern and course of nephrotic syndrome in children. Materials and Methods: The study was a retrospective analysis of medical records of diagnosed nephrotic syndrome patients in the Paediatrics and Nephrology Departments of a Tertiary Care Medical college hospital. The patients were prospectively followed-up for a period of two years. A total of 90 patients were enrolled into the study and their case records were systematically reviewed to obtain the details regarding age, sex distribution, number of admissions, hospital stay during first admission, complications and interim problems, histopathology finding where indicated, diagnostic classifications based on traditional operational definitions, treatment received, duration of remission after first episode and its relation to future relapses and the final outcome were noted and then statistically analysed. Results: Of the 90 cases of nephrotic syndrome, 14 were lost during follow-up, so remaining 76 patients were included. There were 49 males (64.5%) and 27 females (35.5%). Steroid- Sensitive Nephrotic Syndrome (SSNS) was the most common type (59%). It was found that 67 (88.1%) patients had first episode within 1-5 years of age, 31(40.8%) had only 1st time admission, 35 (46%) had 2-4 times admissions, while the rest (13.2%) required more than 4 times admissions. Majority of the cases {48 (63.2%)} had hospital stay between 7-14 days. Infectious complications were the most common (35.3%) and 48 (63.1%) cases showed frequent relapse, while 16 (21%) never had a relapse. The final outcome showed 64 (84.2%) of the cases were in remission, 12 (15.8%) were still relapsing, and there was no mortality. Conclusion: Age of onset for nephrotic syndrome was 5 years in majority of cases. Males were more affected than females. Majority of the patients had hospital stay for 7-14 days. SSNS was the most common type of nephrotic syndrome and Urinary Tract Infection (UTI) was the most common infectious complication. As respiratory and UTIs account for majority of relapses, prevention of respiratory infections by observing respiratory etiquettes, early and aggressive treatment and respiratory protective vaccines will go a long way in prevention of relapses.

Pulmonary Surfactants and the Respiratory-Renal Connection in Steroid Sensitive Nephrotic Syndrome of Childhood

Background: Steroid-sensitive nephrotic syndrome (SSNS) in childhood is usually due to minimal change disease (MCD) and unlike many glomerular conditions, it is commonly precipitated by respiratory infections. Of interest, pulmonary inflammation is known to release surfactants in the blood that can bind SIRPα, which is expressed by podocytes and regulates integrin signaling. We performed studies to determine if surfactant-SIRPα interactions may be occurring in MCD. Methods: Studies included developing a novel model of proteinuria by nasal instillation of toll-like receptor ligands (lipopolysaccharide -LPS- and polyinosinic:polycytidylic acid -Poly:IC-), evaluation of serum and urine from 17 children with SSNS/MCD in relapse or remission, and studies using cultured human podocytes treated with sera from children with MCD in remission or relapse. Results: Children with active SSNS/MCD had elevated surfactant proteins A and D in their sera and elevated urinary SIRPα levels, and both decreased when the subjects were in remission. Sera from subjects with SSNS/MCD in relapse, but not in remission, could activate podocyte SIRPα in vitro , leading to release of Src homology 2 domain containing protein tyrosine phosphatase (SHP-2) and Nephrin dephosphorylation thus leading to the activation of the podocyte. The addition of surfactant protein A to MCD sera from a patient in remission could replicate these findings. Similar data was found in mice with nasal instillation of toll-like receptor 4 and 3 agonists LPS and polyI:C which resulted in elevated serum surfactants and their binding to glomeruli triggering proteinuria. Summary: Our data documents a novel pulmonary-podocyte signaling pathway involving surfactants, SIRPα, SHP-2 and Nephrin dephosphorylation in childhood SSNS/MCD.

Lipoprotein (a) as a Predictor of Steroid Dependence in Paediatric Steroid Sensitive Nephrotic Syndrome

Introduction: Lipoprotein a {Lp(a)} increases in Nephrotic Syndrome (NS). Although the majority of paediatric NS are steroid sensitive, relpase and steroid dependence are commonly seen in this cases. Lp(a) is an LDL-like lipoprotein that consists of an LDL particle to which the glycoprotein apolipoprotein(a) {apo(a)} is attached. Aim: To evaluate the potential of Lp(a), measured on admission, for the prediction of relapse/steroid dependency. Materials and Methods: Children (n=36) with first episode NS were recruited in this prospective observational case-control study and followed up for one year. They were tested at presentation for Lp(a) (mg/dL) and standard tests such as haemoglobin, albumin, protein, cholesterol, triglyceride, and urine protein. Children received standard therapy for NS, and were followed for a period of one year from diagnosis to record days to initial remission, relapse episodes, steroid dependence etc. Patients were categorised as: no relapse (NR), Infrequent Relapse (IFR), frequent relapse (FR) and Steroid Dependent (SD) as per standard definitions. Fifteen healthy volunteers were also tested for lipid profile and Lp(a) levels. Results: Of 36 cases (median age 3 years, 19 males), there were 15NR, 7IFR, 2FR and 12SD. The mean Lp(a) of the NS group (165.2±120.4 mg/dL) was higher than controls (30.52±21.9 mg/dL) (p&lt;0.0001). All the lipid parameters except HDL-cholesterol were significantly higher in the NS group. Within the NS group, Lp(a) showed significant correlation (Spearman-rho) with albumin (p=0.0062,r=0.47), but no correlation with lipid parameters or urine protein. Comparison of Lp(a)levels in the NS groups revealed that the SD patients had a high Lp(a)(222.0±115.7 mg/dL) compared to NR (129.7±120.1 mg/dL) (p=0.02). Conclusion: Concentration of plasma Lp(a) in patients with SDNS was higher compared to patients who did not suffer any relapse, and this concentration may serve as a marker for prediction of SDNS.

Endothelin-1 RS5370 gene polymorphism in primary nephrotic syndrome: A case-control study

IntroductionPrimary nephrotic syndrome (NS) is a common glomerular disease in children. We assessed the genotypes and frequency of the rs5370 allelic variant of the EDN1 gene in children with primary NS. Patients and methodsWe conducted a case-control study in Mansoura University Children's Hospital, Egypt between December 2015 and January 2018. We recruited 50 patients with steroid-sensitive NS (SSNS) and 50 patients with steroid-resistant NS (SRNS) in addition to 100 healthy controls. The patients underwent clinical evaluations and tests including measurement of serum albumin, cholesterol, creatinine and urea levels and a 24-h urinary protein test. We used polymerase chain reaction methods to assess the genotypes of rs5370 variants of the EDN1 gene (GG, GT and TT) and alleles (T and G) in the groups under study. ResultsThe most frequent genotype of the EDN1 gene at the locus of interest in the control group was the GT genotype (88%; P=.001) while the GG genotype was more frequent in the NS group compared to the control group (P=.02). We did not find statistically significant differences between the NS and control groups in regard to the EDN1 rs5370 alleles (P=.69). The GG genotype was more frequent in the SSNS group compared to the SRNS and control groups (P=.03). When we compared allele frequencies between the control, SSNS and SRNS groups, we did not find significant differences (P=.89). The GT genotype was associated with normal blood pressure in children with NS (P=.007), while the GG genotype was associated with hypertension (P<.001). We did not find statistically significant differences in renal histopathology or serum cholesterol levels based on the genotype. ConclusionsThe GG genotype at the rs5370 locus of the EDN1 gene may be associated with an increased risk of primary NS and a better response to steroid therapy.

Analysis of 10 Pediatric Nephrotic Syndrome Cases With Complications of Cerebral Sinovenous Thrombosis.

Background: To analyze the clinical characteristics of nephrotic syndrome (NS) with complications of cerebral sinovenous thrombosis (CSVT) in children.Method: Clinical, radiographic, laboratory, and treatment data obtained from 10 confirmed cases of NS with complications of CSVT were analyzed. All patients were followed up for at least 18 months. CSVT was diagnosed by cerebral computed tomography (CT) and/or magnetic resonance imaging (MRI) with or without magnetic resonance venography (MRV) of the cerebral vessels.Results: Among 10 cases reported, 4 were steroid-sensitive NS with frequent relapse, 5 were steroid-resistant (three of them had renal biopsies showing two minimal change disease and one IgA nephropathy), and 1 was steroid-sensitive with one relapse. Common clinical manifestations were headache or ophthalmodynia complicated by vomiting, dizziness, convulsion, and coma. Neuropathologic signs were positive in some cases. Papilledema appeared in only one case with winding of vein. Cerebrospinal fluid was examined in three cases with elevated pressure but normal cytological and biochemical results. D dimer and fibrinogen levels were elevated while prothrombin time and activated partial thromboplastin time were shortened. Five out of seven cases who had performed cranial CT were suspicious for cerebral thrombosis. Nine cases had cranial MRI with abnormal signs in seven cases. All of the cases received MRV, confirming the diagnosis of CVST.Conclusion: Clinical manifestations of NS with CSVT are not specific but varied. Therefore, CSVT should be considered once nervous manifestations present. MRV is a better method in the diagnosis of CSVT.

Decreased Circulating Transitional B-Cell to Memory B-Cell Ratio Is a Risk Factor for Relapse in Children with Steroid-Sensitive Nephrotic Syndrome

Introduction: A significant proportion of children with SSNS (steroid-sensitive nephrotic syndrome) experience recurrence. Reliable biomarkers to predict flare are currently lacking because the pathogenesis of SSNS remains obscure. Objective: Since B cells may be involved in the pathogenesis of SSNS, we aimed to identify perturbations of B-cell subsets that might predict SSNS relapse. Methods: We measured levels of circulating B-cell subsets in 69 SSNS children by flow cytometry, between 2018 and 2019. We divided them into a relapse group and a nonrelapse group according to whether a relapse occurred within 1 year of follow-up. We used Cox survival analysis to assess correlations between B-cell subsets and relapse. In addition, recurrence-free survival curves were calculated using the Kaplan-Meier method. Results: The proportion of transitional B cells was significantly lower in the relapse group (5.3 ± 5.1% vs. 8.7 ± 4.3% in nonrelapse group, p = 0.007), while the proportion of memory B cells was significantly higher (8.4 ± 3.0% vs. 5.8 ± 3.3% in nonrelapse, p = 0.002). There was a significant decrease in the transitional B-cell to memory B-cell ratio (T/M) in the relapse group (p < 0.001). Univariate analysis revealed that transitional B cells, memory B cells, and the T/M ratio were significantly correlated with relapse in SSNS patients (p < 0.05). Multivariate analysis revealed that only T/M ratio (hazard ratio 0.278, 95% confidence interval 0.085–0.908, p = 0.034) was an independent risk factor for recurrence-free survival in SSNS patients. A cutoff value for the T/M ratio of 1.16 resulted in a sensitivity of 90% and specificity of 80% (area under the curve 0.909; p < 0.001). Kaplan-Meier curves of cumulative relapse-free survival, stratified by this cutoff value, were constructed, which showed that the cumulative relapse-free rates for cutoff values of >1.16 (n = 38) and ≤1.16 (n = 31) were 76.3 and 29.0%, respectively (χ² = 18.416, p < 0.001). Conclusions: Decreased transitional B/memory B ratio is associated with SSNS recurrence in the reported cohort. Thus, it may prove to be a useful marker to predict SSNS relapse in children.

Predictive Value of Serum Interleukins in Children with Idiopathic Nephrotic Syndrome.

Pro-inflammatory cytokines have been suggested in the pathogenesis of idiopathic nephrotic syndrome (INS), with conflicting results. This study was performed to identify alteration of different serum interleukins (ILs) in children with INS, and their predictive value in response to steroid treatment. Three groups of children (27; steroid-sensitive INS, 21; steroid-resistant INS, and 19 healthy controls) with normal serum C3, negative serologic tests of hepatitis B virus (HBV), hepatitis C virus (HCV), human immune deficiency virus (HIV), and parasitic infections were included in this study. Serum concentrations of IL-1β, IL-2, IL-6, IL-8, IL-13, and IL-18 were measured, using quantitative colorimetric sandwich ELISA kits. Children with secondary nephrotic syndrome, inflammations, systemic disorders, and chronic kidney disease were excluded. The serum concentration of all ILs; except IL-13 and IL-18; was significantly higher in children with INS, compared with the healthy controls. Serum IL-2 had the highest sensitivity of (95.24%) in patients with INS. All of the serum ILs had acceptable accuracy in children with INS, compared with the control group. The serum concentration of IL-1β, IL-6, and IL-8 was significantly higher in children with steroid-sensitive nephrotic syndrome (SSNS), compared with steroid-resistant nephrotic syndrome (SRNS). All of these ILs had acceptable accuracy for the prediction of steroid response in patients with INS. Our findings suggested the pathogenic role of pro-inflammatory cytokines in children with INS, of which IL-1β, IL-6, and IL-8 were accurate biomarkers for the prediction of steroid response in these patients.

Polimorfismo rs5370 del gen de la endotelina-1 en el síndrome nefrótico primario: estudio de casos y controles

IntroductionPrimary nephrotic syndrome (NS) is a common glomerular disease in children. We assessed the genotypes and frequency of the rs5370 allelic variant of the EDN1 gene in children with primary NS. Patients and methodsWe conducted a case-control study in Mansoura University Children's Hospital, Egypt, between December 2015 and January 2018. We recruited 50 patients with steroid-sensitive NS (SSNS) and 50 patients with steroid-resistant NS (SRNS) in addition to 100 healthy controls. The patients underwent clinical evaluations and tests including measurement of serum albumin, cholesterol, creatinine and urea levels and a 24-hour urinary protein test. We used polymerase chain reaction methods to assess the genotypes of rs5370 variants of the EDN1 gene (GG, GT and TT) and alleles (T and G) in the groups under study. ResultsThe most frequent genotype of the EDN1 gene at the locus of interest in the control group was the GT genotype (88%; P=.001) while the GG genotype was more frequent in the NS group compared to the control group (P=.02). We did not find statistically significant differences between the NS and control groups in regard to the EDN1 rs5370 alleles (P=.69). The GG genotype was more frequent in the SSNS group compared to the SRNS and control groups (P=.03). When we compared allele frequencies between the control, SSNS and SRNS groups, we did not find significant differences (P=.89). The GT genotype was associated with normal blood pressure in children with NS (P=.007), while the GG genotype was associated with hypertension (P<.001). We did not find statistically significant differences in renal histopathology or serum cholesterol levels based on the genotype. ConclusionsThe GG genotype at the rs5370 locus of the EDN1 gene may be associated with an increased risk of primary NS and a better response to steroid therapy.

Impaired thiol/disulphide homoeostasis in children with steroid-sensitive nephrotic syndrome.

Abnormal thiol/disulphide homoeostasis (TDH) is responsible for the pathogenesis of various diseases. We aimed to examine the TDH in children with steroid-sensitive nephrotic syndrome (SSNS). A total of 131 children, 60 with SSNS and 71 healthy controls, participated in the study. Plasma total thiol (TT), native thiol (SH) and disulphide (SS) levels in the SSNS during remission and control groups were estimated using a new method developed by Erel and Neselioglu. Albumin, TT, SH levels and SH/TT ratio were decreased, whereas SS/SH and SS/TT ratios were elevated in SSNS group compared with control group. However, there was no significant difference in SS levels between the two groups. Albumin level was positively correlated with TT, SH and SS levels in the SSNS group. We found that TDH shifts in favour of oxidants in children with SSNS in remission. This shift indicates that SSNS patients are exposed to augmented oxidative stress.

Cardiac functions in children with steroid-sensitive nephrotic syndrome.

The aim of the present study was to evaluate the presence of cardiac systolic and diastolic dysfunction in pediatric patients with steroid-sensitive nephrotic syndrome (NS). The study population consisted of 19 patients with debut-relapse of NS aged 1-18years and 30 sex and age-matched healthy controls. Blood and urine samples, two M-mode conventional echocardiograms and tissue Doppler velocity imaging were evaluated in both attack and remission periods. With regard to conventional pulse wave Doppler (cPWD), steroid-sensitive NS patients (both in debut / relapse and in remission periods) had a higher peak of late diastolic flow velocities (A peak), and patients in debut / relapse had a lower E/A ratio than the control group, indicating diastolic dysfunction (overall P = 0.003 and P = 0.006, respectively). Based on tissue Doppler velocity imaging echocardiography results, patients in debut/relapse had a higher A' and a lower E'/A' ratio (overall P < 0.001 and P = 0.001, respectively). There was also a significant difference in the cPWD E/TDI E' ratio between the patients showing an increased cPWD E/TDI E' ratio in remission periods compared to in debut/relapse periods (P = 0.09). The albumin levels were positively correlated with E'/A' and E/ E' ratio (r = 0.609; P = 0.007, r = 0.472; P = 0.041 respectively). Systolic cardiac functions are preserved but diastolic functions are affected in steroid-sensitive NS patients both in debut/relapse and in remission periods in a relatively short time. The persistence of left ventricular (LV) dysfunction during the remission period requires special attention during the follow up for early detection of cardiac abnormalities.

Phenotypes of B-Lymphocytes as a Predictor of Steroid Response in Idiopathic Nephrotic Syndrome.

Introduction: The pathogenesis of Idiopathic nephrotic syndrome (INS) is not clear, where the role of B-cells is not yet illustrated. Aim of the study: To evaluate B- cells subsets as a predictor of steroid therapy sensitivity among INS at initial onset. Methods: 45 children with idiopathic nephrotic syndrome were recruited in a follow- up study, patients were divided into steroid-sensitive nephrotic syndrome (SSNS) and steroid-resistant nephrotic syndrome (SRNS) groups based on their sensitivities to steroids. Venous blood samples were drawn from all children for assessment of memory B- cell population before and after one year of steroid therapy. Results: We found statistically significant relation between steroid response and total memory CD19+ CD27+B cell at disease onset where it was higher in SSNS group. Our results showed The best cut-off of total CD19+ B cells in predicting steroid response was ≥32.7 with an area under curve (AUC) of 0.445, a sensitivity of 43.9%, a specificity of 50%, a positive predictive value (PPV) of 90%, a negative predictive value (NPV) of 8% and an accuracy of 44.4% (p>0.05) We also found that The best cut-off of CD19+ CD 27+ total memory B cells in predicting steroid response was ≥32 with an AUC of 0.817, a sensitivity of 78%, a specificity of 75%, a PPV of 97%, a NPV of 25% and an accuracy of 77.8% (p < 0.05). Conclusion: CD19+ CD 27+ total memory B cells could help in predicting steroid response among INS patients with a cut-off of total CD 19+B cells above 32.7 and PPV of 90% , a cut-off above 32 in CD19+ CD +27 total memory cells and PPV 97%.

Selenium level in steroid-resistant and steroid-sensitive nephrotic syndrome

Background The mechanisms of pathogenesis of steroid-resistant nephrotic syndrome (SRNS) and steroid-sensitive nephrotic syndrome (SSNS) are not well understood. Antioxidants, such as glutathione peroxidase enzyme (GPx) and its cofactor, selenium, are thought to slow the progress of nephrotic syndrome (NS).&#x0D; Objective To compare selenium levels in SRNS and SSNS pediatric patients.&#x0D; Methods This cross-sectional study was conducted in 51 SRNS and 30 SSNS patients, aged 2 to 18 years, who visited the Pediatric Nephrology Outpatient Clinic at Cipto Mangunkusumo Hospital, Jakarta. Subjects were included by consecutive sampling. Selenium was measured on venous blood using GC tools MS ™ (Agilent technologies, inc.).&#x0D; Results Median selenium levels in SRNS patients were 92 (range 42-154) μg/L and in SSNS patients were 93 (range 69-193) μg/L.&#x0D; Conclusion Selenium levels in SRNS and SSNS patients were not significantly different.

Results of the PROPINE randomized controlled study suggest tapering of prednisone treatment for relapses of steroid sensitive nephrotic syndrome is not necessary in children

Corticosteroid-related toxicity in children with steroid-sensitive nephrotic syndrome is primarily related to the cumulative dose of prednisone. To optimize treatment of relapses, we conducted the PROPINE study, a multicentric, open-label, randomized, superiority trial. Seventy-eight relapsing children aged 3-17 years who had not received steroid-sparing medications during the previous 12 months were randomized to receive, from day five after remission, either 18 doses of 40 mg/m2 of prednisone on alternate days (short arm), or the same cumulative dose tapered over double the time (long arm). Patients were monitored with an ad-hoc smartphone application, allowing daily reporting. The primary outcome was the six-month relapse rate at which time, 23/40 and 16/38 patients had relapsed in the long and short arms, respectively (no significant difference). Additionally, 40/78 patients were also enrolled in a secondary crossover study and were allocated to the opposite arm. Altogether, at six months, the relapse rate was 32/40 and 28/40 in the long and short arms, respectively (no significant difference). A post-hoc analysis excluding 30 patients treated with low-dose prednisone maintenance therapy failed to show significant differences between the two arms. No differences in adverse events, blood pressure and weight gain were observed. Thus, our data do not support the prescription of prolonged tapering schedules for relapses of steroid-sensitive nephrotic syndrome in children.

Expression profiling of cultured podocytes exposed to nephrotic plasma reveals intrinsic molecular signatures of nephrotic syndrome.

Background Nephrotic syndrome (NS) is a common renal disorder in children attributed to podocyte injury. However, children with the same diagnosis have markedly variable treatment responses, clinical courses, and outcomes, suggesting molecular heterogeneity.Purpose This study aimed to explore the molecular responses of podocytes to nephrotic plasma to identify specific genes and signaling pathways differentiating various clinical NS groups as well as biological processes that drive injury in normal podocytes. Methods Transcriptome profiles from immortalized human podocyte cell line exposed to the plasma of 8 subjects (steroid-sensitive nephrotic syndrome [SSNS], n=4; steroid-resistant nephrotic syndrome [SRNS], n=2; and healthy adult individuals [control], n=2) were generated using microarray analysis. Results Unsupervised hierarchical clustering of global gene expression data was broadly correlated with the clinical classification of NS. Differential gene expression (DGE) analysis of diseased groups (SSNS or SRNS) versus healthy controls identified 105 genes (58 up-regulated, 47 down-regulated) in SSNS and 139 genes (78 up-regulated, 61 down-regulated) in SRNS with 55 common to SSNS and SRNS, while the rest were unique (50 in SSNS, 84 genes in SRNS). Pathway analysis of the significant (P≤0.05, -1≤ log2 FC ≥1) differentially expressed genes identified the transforming growth factor-β and Janus kinase-signal transducer and activator of transcription pathways to be involved in both SSNS and SRNS. DGE analysis of SSNS versus SRNS identified 2,350 genes with values of P≤0.05, and a heatmap of corresponding expression values of these genes in each subject showed clear differences in SSNS and SRNS. Conclusion Our study observations indicate that, although podocyte injury follows similar pathways in different clinical subgroups, the pathways are modulated differently as evidenced by the heatmap. Such transcriptome profiling with a larger cohort can stratify patients into intrinsic subtypes and provide insight into the molecular mechanisms of podocyte injury.

A global antiB cell strategy combining obinutuzumab and daratumumab in severe pediatric nephrotic syndrome.

BackgroundSteroid-sensitive nephrotic syndrome (SSNS) is, in most patients, a chronic disease with 80% experiencing at least one relapse after first flare. B cell depletion using rituximab is effective in preventing relapse in steroid-dependent (SDNS) patients but fails to maintain long-term remission following B cell recovery, possibly due to development of autoreactive long-lived plasma cells. We investigated sequential combination of antiCD20 antibody targeting all B cell subsets, and antiCD38 antibody with high plasma cell cytotoxicity in patients with uncontrolled SDNS after failure of one or several attempts at B cell depletion.MethodsFourteen patients with median disease duration 7.8 years received 1000 mg/1.73 m2 obinutuzumab followed by 1000 mg/1.73 m2 daratumumab 2 weeks later. Oral immunosuppression was discontinued within 6 weeks, and biological monitoring performed monthly until B cell recovery.ResultsMedian age at treatment was 11.0 [IQR 10.4–14.4] years. B cell depletion was achieved in all patients, and B cell reconstitution occurred in all at median 9.5 months after obinutuzumab injection. After median follow-up 20.3 months (IQR 11.5–22.6), 5/14 patients relapsed including 4 within 100 days following B cell repletion. Relapse-free survival was 60% at 24 months from obinutuzumab infusion. Mild infusion reactions were reported in 3/14 patients during obinutuzumab and 4/14 during daratumumab infusions. Mild transient neutropenia (500–1000/mm3) occurred in 2/14 patients. Intravenous immunoglobulins were given to 12/14 patients due to hypogammaglobulinemia. Low IgA and IgM levels were noted in 8 and 14 patients, respectively. No severe infection was reported.ConclusionGlobal antiB cell strategy combining obinutuzumab and daratumumab induces prolonged peripheral B cell depletion and remission in children with difficult-to-treat SDNS.Electronic supplementary materialThe online version of this article (10.1007/s00467-020-04811-0) contains supplementary material, which is available to authorized users.

Novel insights in the genetics of steroid-sensitive nephrotic syndrome in childhood.

Steroid-sensitive nephrotic syndrome (SSNS) is the most common form of nephrotic syndrome in childhood and there is growing evidence that genetics play a role in the susceptibility for the disease. Familial clustering has been observed and hasled to several studies on familial SSNS trying to identify a monogenic cause of the disease. Until now, however, none of these have provided convincing evidence for Mendelian inheritance. This and the phenotypic variability within SSNS suggest a complex inheritance pattern, where multiple variants and interactions between those and the environment play roles in disease development. Genome-wide association studies (GWASs) have been used to investigate this complex disease. We herein highlight new insights in the genetics of the disease provided by GWAS and identifyhow theseinsights fit into our understanding of the pathogenesis of SSNS.

Comprehensive Review of Steroid-Sensitive Nephrotic Syndrome Genetic Risk Loci and Transcriptional Regulation as a Possible Mechanistic Link to Disease Risk

IntroductionThe etiology of steroid-sensitive nephrotic syndrome (SSNS) is not well understood. Genetic studies have established common single nucleotide polymorphisms (SNPs) that are associated with increased SSNS disease risk. We review previous genetic association studies of SSNS and nominate particular transcriptional regulators and immune cells as potential key players in the etiology of this disease.MethodsA list of SNPs associated with SSNS was compiled from published genome wide association and candidate gene studies. The Regulatory Element Locus Intersection (RELI) tool was used to calculate the enrichment of the overlap between disease risk SNPs and the genomic coordinates of data from a collection of >10,000 chromatin immunoprecipitation sequencing experiments.ResultsAfter linkage disequilibrium expansion of the previously reported tag associated SNPs, we identified 192 genetic variants at 8 independent risk loci. Using the Regulatory Element Locus Intersection algorithm, we identified transcriptional regulators with enriched binding at SSNS risk loci (10-05 < Pcorrected < 10-124), including ZNF530, CIITA, CD74, RFX5, and ZNF425. Many of these regulators have well-described roles in the immune response. RNA polymerase II binding in B cells also demonstrated enriched binding at SSNS risk loci (10-37<Pcorrected<10-5).ConclusionSSNS is a complex disease, and immune dysregulation has been previously implicated as a potential underlying cause. This assessment of established SSNS risk loci and analysis of possible function implicates transcriptional dysregulation, and specifically particular transcriptional regulators with known roles in the immune response, as important in the genetic etiology of SSNS.

Prevalence of NPHS2 gene R229Q polymorphism in Bangladeshi children with nephrotic syndrome

BackgroundLimited and contradictory pharmacogenetic studies of NPHS2 gene R229Q polymorphism in nephrotic syndrome (NS) children of different ethnicities steered us to investigate the genotype frequency and associated risk of this polymorphism in Bangladeshi NS children. MethodsA prospective case-control study was conducted which comprised a total of 142 children having nephrotic syndrome (NS), divided into 2 groups: case group consisted of 40 children with steroid-resistant nephrotic syndrome (SRNS), and control group involved 102 children with steroid-sensitive nephrotic syndrome (SSNS). Both were genotyped by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method for R229Q polymorphism. ResultsThe results indicate the presence of R229Q polymorphism in 27.50% of SRNS and 12.75% of SSNS children. SRNS children possess 2.94-fold greater risk (p = 0.025) of carrying Arg/Gln genotype compared to SSNS children. Moreover, R229Q variant in SRNS children was observed as in a compound heterozygous form with p.Ala297Val located in exon 8. Age of onset (4–6 years) presents as a significant contributing factor (adjusted OR = 1.06; 95% CI = 1.023–1.094; p = 0.001) for SRNS susceptibility in Bangladeshi children. Contrarily, though the incidence of SRNS was higher in male children than female (80% vs 20%), gender remains to be a neutral factor (p = 0.257) in relation to SRNS susceptibility. ConclusionCompound heterozygosity of NPHS2 p.R229Q gene variant with p.Ala297Val may cause pathogenic SRNS in Bangladeshi children. Large scale studies are warranted to establish the genotype-phenotype correlation. It is recommended to screen for p.R229Q first and, if positive, for p.Ala297Val in Bangladeshi SRNS children.